Method for producing ortho-alkylated benzoic acid derivatives

ABSTRACT

The invention relates to a process for the preparation of ortho-alkylated benzoic acid derivatives of the formula I  
                 
 
     characterized in that an aryl bromide of the formula II  
                 
 
     is reacted with a secondary or tertiary organolithium compound and CO 2 .

[0001] The invention relates to a process for the preparation ofortho-alkylated benzoic acid derivatives of the formula I

[0002] in which

[0003] A is an alkyl radical having from 1 to 4 carbon atoms,

[0004] characterized in that an aryl bromide of the formula II

[0005] in which A is as defined in formula I,

[0006] is reacted with a secondary or tertiary organolithium compoundand CO₂.

[0007] Ortho-alkylated benzoic acid derivatives of the formula I areimportant intermediates in industrial organic synthesis, e.g. in thepreparation of fine chemicals, dyes and crop-protection compositions.They are also important intermediates in the preparation of medicaments,in particular in the preparation of inhibitors of the cellular Na⁺/H⁺antiporter, which are known from EP 0 699 666 A1 or EP 0 758 644. Inparticular, 4-chloro-2-methylbenzoic acid is an intermediate in thesynthesis ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide,known from EP 0 699 666 A1 orN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, known fromEP 0 758 644.

[0008] From classical organic synthesis (see on this subject standardworks on organic synthesis, such as Houben-Weyl, Methoden derorganischen Chemie [Methods in Organic Chemistry], Georg-Thieme-Verlag,Stuttgart, or Beyer, Walter, Lehrbuch der organischen Synthese [Handbookof Organic Synthesis], S. Hirzel Verlag, Stuttgart), the preparation ofortho-alkylated benzoic acid derivatives from aniline derivatives bydiazotization, Sandmeyer reaction and subsequent nitrile hydrolysis, orby ortho-metalation and subsequent alkylation of benzoic acidderivatives, is known. For economic and ecological reasons, thesemultistage synthesis sequences are unpracticable for industrialapplication.

[0009] H. Gilman et al., J. Am. Chem. Soc. 1940, 62, 2327f. describesthe synthesis of benzoic acid derivatives by lithiation of thecorresponding aryl bromides and subsequent carboxylation. Thepreparation of 2-methyl-benzoic acid by reaction of o-bromotoluene withn-butyllithium and subsequent carboxylation with solid CO₂ achieves ayield of 83.8%. The reaction of 4-chlorobromobenzene with n-butyllithiumand CO₂ gives 4-chlorobenzoic acid with a 90% yield.

[0010] Preparation of the ortho-alkylated compounds of the formula I, inparticular of 4-chloro-2-methylbenzoic acid, is impossible using thesynthesis described above. Under the reaction conditions described in H.Gilman et al., J. Am. Chem. Soc. 1940, 62, 2327f., and using thecustomary lithiation reagents n-butyllithium, n-hexyllithium,phenyllithium or methyllithium, the desired reaction does not take placeat all or only with a very low yield.

[0011] These findings are further supported by the synthesis of4-chloro-2-methylbenzoic acid which is described in U.S. Pat. No.3,910,947. Firstly, 2-methyl-4-chloroaniline is diazotized and thediazonium salt is scavenged with KI to synthesize the very reactive2-iodo-4-chlorotoluene, which is immediately converted into4-chloro-2-methylbenzoic acid by reaction with n-butyllithium and CO₂.The choice of the very reactive aryl iodide over the less expensive andmore readily available bromine derivative confirms that it was hithertoimpossible to convert the aryl bromides into the desired benzoic acidderivatives of the formula I in a satisfactory yield.

[0012] The object of the invention was therefore to develop a processfor the preparation of ortho-alkylated benzoic acid derivatives of theformula I which permits the use of aryl bromides.

[0013] Surprisingly, it has been found that the reaction of the arylbromides of the formula II with a secondary or tertiary organolithiumcompound as metalation agent takes place with a yield which is improvedcompared with the prior art or is very good.

[0014] As a result, we have provided a way of preparing theortho-alkylated benzoic acid derivatives of the formula I by a reaction,which is easy to handle even on an industrial scale, as a one-potsynthesis under mild conditions and using bromine derivatives of theformula II, which are less expensive than the aryl iodides.

[0015] The invention therefore provides a process for the preparation ofortho-alkylated benzoic acid derivatives of the formula I

[0016] characterized in that an aryl bromide of the formula II

[0017] is reacted with a secondary or tertiary organolithium compoundand CO₂.

[0018] The invention further provides a process for the preparation ofortho-alkylated benzoic acids of the formula I, characterized in that asecondary organolithium compound chosen from the group consisting ofsec-butyllithium, isopropyllithium, sec-amyllithium, 4-heptyllithium,cyclopropyllithium or cyclohexyllithium or a tertiary organolithiumcompound chosen from the group consisting of tert-butyllithium,tert-amyllithium, triethylmethyllithium, 1-methylcyclopentyllithium oradamantyllithium is used.

[0019] The invention further provides a process for the preparation ofortho-alkylated benzoic acid derivatives of the formula I, characterizedin that the reaction is carried out at temperatures between −100° and+50° C., and the reaction product is precipitated by adding an acid.

[0020] The invention further provides a process for the preparation ofortho-alkylated benzoic acid derivatives of the formula I, characterizedin that the reaction is carried out in an inert solvent chosen from thegroup consisting of diethyl ether, methyl tert-butyl ether,tetrahydrofuran, dioxane, toluene, hexane, petroleum ether or mixturesthereof.

[0021] The invention further provides a process for the preparation ofortho-alkylated benzoic acid derivatives of the formula I, characterizedin that the aryl bromide of the formula II is introduced into an inertsolvent, the secondary or tertiary organolithium compound is added, thisreaction mixture is added dropwise to a CO₂-saturated solvent, and themixture is again saturated with CO₂.

[0022] The invention preferably provides a process for the preparationof 4-chloro-2-methylbenzoic acid, characterized in that2-bromo-5-chlorotoluene is reacted with a secondary or tertiaryorganolithium compound and CO₂.

[0023] The invention particularly preferably provides a process for thepreparation of 4-chloro-2-methylbenzoic acid, characterized in that

[0024] a) 2-bromo-5-chlorotoluene is reacted with sec-butyllithium andCO₂,

[0025] b) the reaction is carried out at temperatures between −100° and+50° C., and 4-chloro-2-methylbenzoic acid is precipitated by adding anacid,

[0026] c) the reaction is carried out in an inert solvent chosen fromthe group consisting of diethyl ether, methyl tert-butyl ether,tetrahydrofuran, dioxane, toluene, hexane, petroleum ether or mixturesthereof, and

[0027] d) the 2-bromo-5-chlorotoluene is introduced into an inertsolvent, the sec-butyllithium is added, this reaction mixture is addeddropwise to a CO₂-saturated solvent, and the mixture is again saturatedwith CO₂.

[0028] The invention further provides for the use of4-chloro-2-methylbenzoic acid prepared from the process described aboveas intermediate in the synthesis ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide.

[0029] The invention also provides a process for the preparation ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamidecharacterized in that

[0030] in stage a) 2-bromo-5-chlorotoluene is reacted with a secondaryor tertiary organolithium compound, particularly preferablysec-butyllithium, and CO₂ to give 4-chloro-2-methylbenzoic acid,

[0031] in stage b) 4-chloro-2-methylbenzoic acid is reacted withchlorosulfonic acid, sodium sulfite and methyl iodide to give2-methyl-4-chloro-5-methylsulfonylbenzoic acid,

[0032] in stage c) 2-methyl-4-chloro-5-methylsulfonylbenzoic acid isreacted with benzylamine to give4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,

[0033] in stage d) 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acidis esterified with an alcohol to give the corresponding ester of4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,

[0034] in stage e) the ester from stage d) is reduced to give thecorresponding 4-amino-5-methylsulfonyl-2-methylbenzoic ester,

[0035] in stage f) 4-amino-5-methylsulfonyl-2-methylbenzoic ester isreacted with dimethoxytetrahydrofuran to give2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoic ester, and

[0036] in stage g) 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoic esteris reacted with guanidine to giveN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide.

[0037] In stage d) preference is given to using an aliphatic alcoholhaving from 1 to 6 carbon atoms, such as, for example, methanol,ethanol, propanol, butanol, pentanol or hexanol. Particular preferenceis given to using methanol.

[0038] The invention further provides for the use of4-chloro-2-methylbenzoic acid, prepared from the process describedabove, as intermediate in the synthesis ofN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide.

[0039] The invention also provides a process for the preparation ofN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide,characterized in that

[0040] in stage a) 2-bromo-5-chlorotoluene is reacted with a secondaryor tertiary organolithium compound, particularly preferablysec-butyllithium, and CO₂ to give 4-chloro-2-methylbenzoic acid,

[0041] in stage b) 4-chloro-2-methylbenzoic acid is reacted withchlorosulfonic acid, sodium sulfite and methyl iodide to give2-methyl-4-chloro-5-methylsulfonylbenzoic acid,

[0042] in stage c) 2-methyl-4-chloro-5-methylsulfonylbenzoic acid isreacted with sodium methylthiolate and then oxidized with an oxidizingagent to give 2-methyl-4,5-di(methylsulfonyl)benzoic acid,

[0043] in stage d) 2-methyl-4,5-di(methylsulfonyl)benzoic acid isreacted with thionyl chloride to give2-methyl-4,5-di(methylsulfonyl)benzoyl chloride, and

[0044] in stage e) 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride isreacted with guanidinium chloride to giveN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide.

[0045] Preferred oxidizing agents in stage c) are H₂O₂, O₂ or sodiumperborate. Very particular preference is given to using sodiumperborate.

[0046] The abbreviations used have the following meanings: n-Bu n-butylEt ethyl Me methyl MTB methyl tert-butyl THF tetrahydrofuran h hours

[0047] In the above formulae, A is alkyl and has from 1 to 4, preferably1, 2 or 3, carbon atoms. Alkyl is preferably methyl, also ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. Particularpreference is given to methyl.

[0048] In the above formulae, the Cl substituent is preferably in the3-, 4-, 5- or 6-position, particularly preferably in the 4-positionrelative to the position of the carboxyl group of the formula I.

[0049] The aryl bromides of the formula II are commercially available orcan be prepared by methods known per se, as described, for example, inHouben-Weyl, Methoden der Organ. Chemie [Methods in Organic Chemistry].

[0050] CO₂ is used in solid or gaseous form.

[0051] The invention also provides a process, as described,characterized in that secondary organolithium compounds chosen from thegroup consisting of sec-butyllithium, isopropyllithium, sec-amyllithium,4-heptyllithium, cyclopropyllithium or cyclohexyllithium or a tertiaryorganolithium compound chosen from the group consisting oftert-butyllithium, tert-amyllithium, triethylmethyllithium,1-methylcyclopentyllithium or adamantyllithium are used.

[0052] Preference is given to using secondary organolithium compoundschosen from the group consisting of sec-butyllithium, isopropyllithium,sec-amyllithium, 4-heptyllithium, cyclopropyllithium orcyclohexyllithium; particular preference is given to usingsec-butyllithium.

[0053] The secondary or tertiary organolithium compounds listed aboveare commercially available or can be prepared by methods known per se,as described, for example, in Houben-Weyl, Methoden der Organ. Chemie[Methods in Organic Chemistry].

[0054] The invention also provides a process, as described,characterized in that the reaction is carried out at temperaturesbetween −100° and +50° C. Preference is given to the temperature rangebetween −50° and +40°, particular preference to the temperature rangebetween −20° and +50° C., very particular preference to the temperaturerange between −15° and 0° C.

[0055] The invention also provides a process, as described,characterized in that the reaction product, following customary work-upof the reaction mixture, is precipitated using acid. Customary work-upmeans: NaOH (10%) is added to the reaction mixture, the phases areseparated, the organic phase is washed with NaOH (10%), and the aqueousphases are extracted with the inert solvent and separated off. The acidis chosen from a group of acids which include organic acids, preferablyformic acid, acetic acid or propionic acid, or inorganic acids,preferably sulfuric acid, nitric acid, hydrohalic acids such ashydrochloric acid or hydrobromic acid, or phosphoric acids such asorthophosphoric acid. Particular preference is given to usinghydrochloric acid.

[0056] The invention also provides a process, as described,characterized in that the reaction is carried out in an inert solventchosen from the group consisting of diethyl ether, MTB ether, THF,dioxane, toluene, hexane, petroleum ether or mixtures thereof.Particular preference is given to methyl tert-butyl ether.

[0057] The invention also provides a process, as described,characterized in that the aryl bromide of the formula II is introducedinto an inert solvent chosen from the group consisting of diethyl ether,MTB ether, THF, dioxane, toluene, hexane, petroleum ether or mixturesthereof, particularly preferably MTB ether, the secondary or tertiaryorganolithium compound is added, this reaction mixture is added dropwiseto a preferred volume of CO₂-saturated solvent and the mixture is againsaturated with CO₂.

[0058] According to the process of the invention, the yields ofortho-alkylated benzoic acid derivatives of the formula I are generallybetween 30% and 90% when secondary or tertiary organolithium compoundsare used, between 50% and 90% when secondary organolithium compounds areused, in particular between 70% and 90% when sec-butyllithium is used.Laborious purification steps by, for example, repeated recrystallizationcan be omitted. All temperatures above and below are given in ° C. Thecontents were determined, for example, after drying the crystals at 55°.

[0059] The invention also provides for the use of4-chloro-2-methylbenzoic acid, prepared by the process described above,as intermediate in the synthesis ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide,known from EP 0 699 666 A1. Other intermediates of this synthesissequence ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide,starting from the intermediate 4-chloro-2-methylbenzoic acid, are2-methyl-4-chloro-5-methylsulfonylbenzoic acid, methyl2-methyl-4-chloro-5-methylsulfonylbenzoate and methyl2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate.

[0060] Accordingly, the invention also provides a process for thepreparation ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamine,characterized in that in the first stage a) according to the invention2-bromo-5-chlorotoluene is reacted with a secondary or tertiaryorganolithium compound, particularly preferably sec-butyllithium, andCO₂ to give the first intermediate 4-chloro-2-methylbenzoic acid,

[0061] in stage b) a methylsulfonyl group is introduced by reacting4-chloro-2-methylbenzoic acid with chlorosulfonic acid, sodium sulfiteand methyl iodide to give the corresponding intermediate2-methyl-4-chloro-5-methylsulfonylbenzoic acid,

[0062] in stage c) the chlorine substituent is converted into abenzylamino group by reacting 2-methyl-4-chloro-5-methylsulfonylbenzoicacid with benzylamine to give the corresponding intermediate4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,

[0063] in stage d) the free acid from stage c) is esterified with analcohol, in particular methanol, and the corresponding intermediate4-benzylamino-5-methylsulfonyl-2-methylbenzoate is obtained,

[0064] in stage e) the benzyl protective group is cleaved off byreduction to give the corresponding intermediate4-amino-5-methylsulfonyl-2-methylbenzoate,

[0065] in stage f) the pyrrole group is introduced by reacting4-amino-5-methylsulfonyl-2-methylbenzoate with dimethoxytetrahydrofuranand, correspondingly, the intermediate2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate is obtained andfinally, as described in EP 0 699 666 (p. 8, line 19 to p. 10, line 1),

[0066] in stage g) by reaction of methyl2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate with guanidine to givethe end-productN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide,the guanidino group is introduced.

[0067] The invention also provides for the use of4-chloro-2-methylbenzoic acid, prepared by the process described above,as intermediate in the synthesis ofN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, known fromEP 0 758 644 A1. Other intermediates of this synthesis sequence ofN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, startingfrom the intermediate 4-chloro-2-methylbenzoic acid, are2-methyl-4-chloro-5-methylsulfonylbenzoic acid,2-methyl-4,5-di(methylsulfonyl)benzoic acid and2-methyl-4,5-di(methylsulfonyl)benzoyl chloride.

[0068] Accordingly, the invention also provides a process for thepreparation ofN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamine,characterized in that in the first stage a) according to the invention2-bromo-5-chlorotoluene is reacted with a secondary or tertiaryorganolithium compound, particularly preferably sec-butyllithium, andCO₂ to give the first intermediate 4-chloro-2-methylbenzoic acid, instage b) a methylsulfonyl group is introduced by reacting4-chloro-2-methylbenzoic acid with chlorosulfonic acid, sodium sulfiteand methyl iodide to give the corresponding intermediate2-methyl-4-chloro-5-methylsulfonylbenzoic acid,

[0069] in stage c) the chlorine substituent is converted into a secondmethylsulfonyl group by reacting2-methyl-4-chloro-5-methylsulfonylbenzoic acid with sodiummethylthiolate and then oxidizing the thioether with an oxidizing agent,in particular sodium perborate, to give the corresponding intermediate2-methyl-4,5-di(methylsulfonyl)benzoic acid,

[0070] in stage d) the free acid from stage c) is converted usingthionyl chloride into the acid chloride2-methyl-4,5-di(methylsulfonyl)benzoyl chloride as intermediate, and

[0071] in stage e) finally, as described in EP 0 758 644 (p.9, lines10-20), by reaction of 2-methyl-4,5-di(methylsulfonyl)benzoyl chloridewith guanidinium chloride to give the end-productN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, theguanidino group is introduced.

[0072] In the examples below and also in the above statements, thetemperature is given in ° C. The pH corresponds to the base-tenlogarithm of the H⁺ ion concentration.

EXAMPLE 1

[0073] At a temperature of −18°, 728 ml of sec-butyllithium are added toa solution of 104.8 g of 2-bromo-5-chlorotoluene in 500 ml of MTB etherover the course of 30 min. The suspension is then added dropwise overthe course of 20 min to 750 ml of CO₂-saturated MTB ether and saturatedagain for 15 min with gaseous CO₂. After a reaction time of 1 h attemperatures between −15° and −5°, 500 ml of NaOH (10%) are added, andthe phases are separated. The organic phase is washed with 250 ml ofNaOH (10%). The combined aqueous phases are extracted with 250 ml of MTBether, adjusted to pH 1-2 with 250.4 g of HCl (37%) and cooled for 1 hat 5° in an ice/ water bath. The crystals are washed with 2×50 ml ofcold water and dried under reduced pressure at 55°. The yield of4-chloro-2-methylbenzoic acid is 90%.

EXAMPLE 2

[0074] For comparison purposes, 2-bromo-5-chlorotoluene is reacted as inExample 1 with the lithiation reagents listed in Table I in the solventsgiven in Table I. The yield of 4-chloro-2-methylbenzoic acid is between0 and 30%. TABLE I Lithiation reagent Solvent Yield [%] MeLi MTB ether 0n-BuLi MTB ether 0 n-BuLi THE 30

EXAMPLE 3

[0075] For comparison purposes, 2-bromo-5-chlorotoluene is reacted as inH. Gilman et al., J. Am. Chem. Soc. 1940, 62, 2327f with n-BuLi inboiling diethyl ether. The yield of 4-chloro-2-methylbenzoic acid is20%.

EXAMPLE 4

[0076] 20.5 g of 2-bromo-5-chlorotoluene dissolved in methyl tert-butylether are reacted as in Example 1 with 143 ml of tert-butyllithium andCO₂. The yield of 4-chloro-2-methylbenzoic acid is 32%.

EXAMPLE 5 Synthesis ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide

[0077] a) At a temperature of -180, 728 ml of sec-butyllithium are addedto a solution of 104.8 g of 2-bromo-5-chlorotoluene in 500 ml of MTBether over the course of 30 min. The suspension is then added dropwiseover the course of 20 min to 750 ml of CO₂-saturated MTB ether andsaturated again for 15 min with gaseous CO₂. After a reaction time of 1h at temperatures between −15° and −5°, 500 ml of NaOH (10%) are added,and the phases are separated. The organic phase is washed with 250 ml ofNaOH (10%). The combined aqueous phases are extracted with 250 ml of MTBether, adjusted to pH 1-2 with 250.4 g of HCl (37%) and cooled for 1 hat 5° in an ice/water bath. The crystals are washed with 2×50 ml of coldwater and dried under reduced pressure at 55°.

[0078] The yield of 4-chloro-2-methylbenzoic acid is 90%.

[0079] b) 722 g of 4-chloro-2-methylbenzoic acid are dissolved in 2.4 lof chlorosulfonic acid at 15° with ice-cooling. After the solution hasbeen heated to 110-115°, it is added dropwise to iced water (20 l) andthen stirred. The precipitate is separated from the mother liquor, driedand then added to a suspension of 1333 g of sodium sulfite in 3 l ofwater. At the same time, the pH is maintained at pH 9 by addition ofsodium hydroxide solution. After the suspension has been stirred at roomtemperature for four hours, the pH is adjusted to pH 1 usinghydrochloric acid. The precipitate is separated from the mother liquorand suspended in 3 l of methanol and 2 l of water. 1.3 l of methyliodide are added to this suspension, and the pH is adjusted to pH 9using sodium hydroxide solution, and the mixture is heated to 40°. Aftermethanol and excess methyl iodide have been distilled off, the mixtureis diluted with water and extracted with ethyl acetate. Some of theethyl acetate is distilled off, the solution which remains is adjustedto pH 1, and the solid which then forms is separated from the motherliquor and dried.

[0080] This gives 2-methyl-4-chloro-5-methylsulfonylbenzoic acid in ayield of 67%.

[0081] c) A solution of 684 g of2-methyl-4-chloro-5-methylsulfonylbenzoic acid and 884 g of benzylaminein 4 l of N-methylpyrrolidine is stirred for 8 h at 160°. The solutionis then poured onto water, the pH is adjusted to pH 12 using sodiumhydroxide solution and extracted with ethyl acetate. The aqueous phaseis adjusted to pH 1 using hydrochloric acid. The precipitate which formsis filtered off and dried overnight. This gives4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid in a yield of 87%.

[0082] d) A suspension of 767 g of4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid in 12 l of methanolis heated to reflux. At the same time, HCl gas is introduced. When thereaction is complete, the clear solution is poured onto ice and theprecipitate which forms is filtered off and dried.

[0083] This gives methyl 4-benzylamino-5-methylsulfonyl-2-methylbenzoatein a yield of 96%.

[0084] e) 68 g of Pd-C (5%) are added to a solution of 683 g of methyl4-benzylamino-5-methylsulfonyl-2-methylbenzoate in 6.8 l of methanol,and 48.4 l of hydrogen are introduced. After 4 h, the mixture is dilutedwith 5 l of methylene chloride, the catalyst is filtered off and some ofthe solvent is distilled off. The precipitate which forms is filteredoff from the concentrated mother liquor and dried. This gives methyl4-amino-5-methylsulfonyl-2-methylbenzoate in a yield of 98%.

[0085] f) 260 ml of dimethoxytetrahydrofuran and 23.8 g of4-chloropyridinium chloride are added to a solution of 385.9 g of methyl4-amino-5-methylsulfonyl-2-methylbenzoate in 6 l of 1,4-dioxane. Thesolution is refluxed until the reaction is complete, and the solvent isdistilled off. The residue is taken up in ethyl acetate and washed withwater and dried over Na₂SO₄. Then, the mixture is decolorized using 15 gof activated carbon under reflux, the activated carbon is filtered offand the ethyl acetate is distilled off. The residue which forms isrecrystallized from methanol. This gives methyl2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate in a yield of 89%.

[0086] g) A solution of 694 g of guanidine and 310 g of methyl2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate in 3 l of methanol isstirred for 3 h at 50°. Then, water is added to the reaction mixture,and the crude product which forms as a result is filtered off andrecrystallized from methanol. This givesN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide ina yield of 66%.

EXAMPLE 6 Synthesis ofN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide

[0087] a) At a temperature of −18°, 728 ml of sec-butyllithium are addedto a solution of 104.8 g of 2-bromo-5-chlorotoluene in 500 ml of MTBether over the course of 30 min. The suspension is then added dropwiseto 750 ml of CO₂-saturated MTB ether over the course of 20 min andsaturated again for 15 min with gaseous CO₂. After a reaction time of 1h at temperatures between −15° and −5° C., 500 ml of NaOH (10%) areadded, and the phases are separated. The organic phase is washed with250 ml of NaOH (10%). The combined aqueous phases are extracted with 250ml of MTB ether, adjusted to pH 1-2 with 250.4 g of HCl (37%) and cooledfor 1 h at 50 in an ice/water bath. The crystals are washed with 2×50 mlof cold water and dried under reduced pressure at 55°.

[0088] The yield of 4-chloro-2-methylbenzoic acid is 90%.

[0089] b) 722 g of 4-chloro-2-methylbenzoic acid are dissolved in 2.4 lof chlorosulfonic acid at 15° with ice-cooling. After the solution hasbeen heated to 110-115°, it is added dropwise to iced water (20 l) andthen stirred. The precipitate is separated from the mother liquor, driedand then added to a suspension of 1333 g of sodium sulfite in 3 l ofwater. At the same time, the pH is maintained at pH 9 by addition ofsodium hydroxide solution. After the suspension has been stirred at roomtemperature for four hours, the pH is adjusted to pH 1 usinghydrochloric acid. The precipitate is separated from the mother liquorand suspended in 3 l of methanol and 2 l of water. 1.3 l of methyliodide are added to this suspension, and the pH is adjusted to pH 9using sodium hydroxide solution, and the mixture is heated to 40° Aftermethanol and excess methyl iodide have been distilled off, the mixtureis diluted with water and extracted with ethyl acetate. Some of theethyl acetate is distilled off, the solution which remains is adjustedto pH 1, and the solid which then forms is separated from the motherliquor and dried.

[0090] This gives 2-methyl-4-chloro-5-methylsulfonylbenzoic acid in ayield of 67%.

[0091] c) 360 g of sodium methylthiolate are added to a solution of 600g of 2-methyl-4-chloro-5-methylsulfonylbenzoic acid in 4 l of DMF, andthe mixture is stirred at 130° until the reaction is complete. Themixture is then poured onto iced water and the pH is adjusted to pH 1using hydrochloric acid. The precipitate which forms is filtered off anddried to give 5-methylsulfonyl-2-methyl-4-methylsulfanylbenzoic acid ina yield of 86%.

[0092] 73 g of 5-methylsulfonyl-2-methyl-4-methylsulfanylbenzoic acidare then dissolved in 1 l of glacial acetic acid, and 180 g of sodiumperborate are added. The reaction mixture is heated for 1 h at aninternal temperature of 65°. Most of the glacial acetic acid isdistilled off and the residue which remains is triturated with ethylacetate. The precipitate which forms is filtered off and washed severaltimes with a 1:1 mixture of ethyl acetate and diethyl ether. To removethe boric acid, the precipitate is stirred in 1 n hydrochloric acid,then filtered off and dried This gives2-methyl-4,5-di(methylsulfonyl)benzoic acid in a yield of 50%.

[0093] d) 400 ml of thionyl chloride are added to 41 g of2-methyl-4,5-di(methylsulfonyl)benzoic acid, and the mixture is refluxeduntil the reaction is complete. The excess thionyl chloride is distilledoff and codistilled several times with toluene.

[0094] This gives 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride in ayield of 98%.

[0095] e) 128.4 g of guanidinium chloride are added to a solution of38.5 g of sodium in 1.3 l of methanol, and the mixture is stirred for 30minutes at room temperature and filtered. After the solvent has beenremoved and the mixture has been washed with toluene, the residue istaken up in 1.3 l of ethylene glycol monomethyl ether and added to asolution of 42.8 g of 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride in1.7 l of ethylene glycol monomethyl ether. The mixture is stirred for 2h at room temperature and diluted with iced water, and 1n hydrochloricacid is added. Then, the mixture is washed with ethyl acetate andadjusted to a pH Of pH 9. Customary work-up and removal of the solventgives, after recrystallization from diethyl ether, theN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide in a yieldof 44%.

Patent claims
 1. Process for the preparation of ortho-alkylated benzoicacid derivatives of the formula I

in which A is an alkyl radical having from 1 to 4 carbon atoms,characterized in that an aryl bromide of the formula II

in which A is as defined in formula I, is reacted with a secondary ortertiary organolithium compound and CO₂.
 2. Process according to claim1, characterized in that a secondary organolithium compound chosen fromthe group consisting of sec-butyllithium, isopropyllithium,sec-amyllithium, 4-heptyllithium, cyclopropyllithium orcyclohexyllithium or a tertiary organolithium compound chosen from thegroup consisting of tert-butyllithium, tert-amyllithium,triethylmethyllithium, 1-methylcyclopentyllithium or adamantyllithium isused.
 3. Process according to claim 1 or 2 for the preparation of4-chloro-2-methylbenzoic acid, characterized in that2-bromo-5-chlorotoluene is used.
 4. Process according to claims 1 to 3,characterized in that the reaction is carried out at temperaturesbetween −100° and +50° C., and the reaction product is precipitated byadding an acid.
 5. Process according to claims 1 to 4, characterized inthat the reaction is carried out in an inert solvent chosen from thegroup consisting of diethyl ether, methyl tert-butyl ether,tetrahydrofuran, dioxane, toluene, hexane, petroleum ether or mixturesthereof.
 6. Process according to claims 1 to 5, characterized in thatthe aryl bromide of the formula II is introduced into an inert solvent,the secondary or tertiary organolithium compound is added, this reactionmixture is added dropwise to a CO₂-saturated solvent, and the mixture isagain saturated with CO₂.
 7. Use of the 4-chloro-2-methylbenzoic acidprepared by the process of claim 3 as intermediate in the synthesis ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide. 8.Process for the preparation ofN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide,characterized in that in stage a) 2-bromo-5-chlorotoluene is reactedwith a secondary or tertiary organolithium compound, particularlypreferably sec-butyllithium, and CO₂ to give 4-chloro-2-methylbenzoicacid, in stage b) 4-chloro-2-methylbenzoic acid is reacted withchlorosulfonic acid, sodium sulfite and methyl iodide to give2-methyl-4-chloro-5-methylsulfonylbenzoic acid, in stage c)2-methyl-4-chloro-5-methylsulfonylbenzoic acid is reacted withbenzylamine to give 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,in stage d) 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid isesterified with an alcohol to give the corresponding ester of4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid, in stage e) theester from stage d) is reduced to give the corresponding4-amino-5-methylsulfonyl-2-methylbenzoic ester, in stage f)4-amino-5-methylsulfonyl-2-methylbenzoic ester is reacted withdimethoxytetrahydrofuran to give2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoic ester, and in stage g)2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoic ester is reacted withguanidine to giveN-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide. 9.Use of 4-chloro-2-methylbenzoic acid prepared from the process describedabove as intermediate in the synthesis ofN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide.
 10. Processfor the preparation ofN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide,characterized in that in stage a) 2-bromo-5-chlorotoluene is reactedwith a secondary or tertiary organolithium compound, particularlypreferably sec-butyllithium, and CO₂ to give 4-chloro-2-methylbenzoicacid, in stage b) 4-chloro-2-methylbenzoic acid is reacted withchlorosulfonic acid, sodium sulfite and methyl iodide to give2-methyl-4-chloro-5-methylsulfonylbenzoic acid, in stage c)2-methyl-4-chloro-5-methylsulfonylbenzoic acid is reacted with sodiummethylthiolate and then oxidized with an oxidizing agent to give2-methyl-4,5-di(methylsulfonyl)benzoic acid, in stage d)2-methyl-4,5-di(methylsulfonyl)benzoic acid is reacted with thionylchloride to give 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride, and instage e) 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride is reacted withguanidinium chloride to giveN-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide.